On Jul. 19, 2023, a team of scientists from the Translational Genomics Research Institute (TGen), part of the City of Hope, and Barrow Neurological Institute have detected these cryptic exons in specific brain cells from ALS and FTD patients carrying a mutation in the C9ORF72 gene.

In some cases, the same genetic mutations occur in both. One of those mutations is a repetitive expansion in the DNA of a gene called C9ORF72. A repetitive expansion is like having a word or phrase repeated over and over again in a sentence. One of the significant changes that happens in the majority of cases of ALS and around half of the cases of FTD, is when a protein called TAR DNA binding protein (TDP-43) clumps together and stops working correctly. When TDP-43 doesn’t function properly, it puts incorrect genetic instructions into the RNA, which are called “cryptic exons.”

Published in Acta Neuropathologica, this was the first time that these disease-linked cryptic exons have been identified in single cells. The findings could help researchers learn more about exactly how cryptic exons affect the cellsﾒ function in ALS and FTD, and about which cells are most vulnerable to TDP-43 dysfunction.

The team found the cryptic exons in two genes–STMN2 and KALRN–in the frontal cortex of the brain in patients with both diseases, with the highest frequency of the cryptic exons for both genes in individuals that had FTD. Some of the cell types identified had previously been linked to FTD, so finding the cryptic exons in them using a different approach “may further confirm them as a vulnerable cell type in the disease,” said Rita Sattler, Ph.D., a Barrow professor in the Department of Translational Neuroscience and study co-author.

The researchers also uncovered some intriguing differences in terms of how likely brain cells were to contain cryptic exons. These differences might be related to the different trajectories of developing either ALS or FTD or both, although the team stressed that it is not possible to know at this stage.